Alpha-1 adrenergic receptors (alpha1-AR) are proteins expressed on the cell surface of muscle cells located in the heart and the walls of blood vessels. Specifically, the activation of alpha1-ARs in muscle cells by epinephrine or norepinephrine leads to an increased. rate and force of heart contraction and increased blood pressure due to constriction of blood vessels. Molecular diversity has given rise to three related proteins, designated the alpha1a -, alpha1b, and alpha1d-ARs. The ability to discriminate these subtypes depends on the ability or selectivity of drugs called antagonists to bind to each of these proteins with different avidity. Clinically, only drugs that possess very high selectivity for individual alpha1-AR subtypes can be used to treat various cardiovascular disease states (elevated blood pressure, hypertrophy and cardiac arrhythmias) that have been attributed to the abnormal functioning of these receptors. Few antagonists of the desired selectivity are currently available for this purpose. Indeed BMY7378 is the only antagonist available that has selectivity for the alpha1d -AR subtype.
Our aim i n this study is to identify the precise locations in the alpha1d-AR that make contact and interact with chemical groups in BMY7378 using a chimeric and site-directed mutagenesis approach. A precise understanding of the chemical interactions between the drug and receptor will enable us to optimize future drug design by altering the drug structure to increase the strength of these unique drug-receptor interactions. Drugs with improved selectivity will be beneficial for the clinical treatment of alpha1-AR-related cardiovascular diseases.
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| McCune, Dan; Gaivin, Robert; Rorabaugh, Boyd et al. (2004) Bulk is a determinant of oxymetazoline affinity for the alpha1A-adrenergic receptor. Receptors Channels 10:109-16 |
